In This Issue

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PD-1 Blockade Is Not Unsafe in Patients with Lung Cancer and COVID-19

• COVID-19 severity and mortality were not • Although PD-1 blockade was not a • This suggests that PD-1 blockade increased in patients with lung cancer risk factor in this population, severity should be used when indicated in patients who received prior PD-1 blockade . and mortality in this group were high . with lung cancer despite COVID-19 .

A key issue in oncology of whether patients received the immunotherapy recently or practice during the COVID-19 at any point prior to infection. There was a slight, statistically pandemic is whether PD-1 insignifi cant numeric increase in severity with PD-1 blockade, blockade affects the severity of but controlling for smoking history—which is an expected COVID-19 in patients with can- imbalance in receipt of prior PD-1 blockade and a risk factor cer. PD-1 blockade may increase for severe COVID-19 outcomes—abolished this correlation. COVID-19 severity by contrib- This work suggests that prior PD-1 blockade is not a clinically uting to hyperactive immune meaningful risk factor for worsened COVID-19 outcomes, responses to SARS-CoV-2 infec- implying that PD-1 blockade should be used when indicated tion—or, alternatively, may reduce despite the pandemic. Larger studies are needed to more fully severity by enhancing control of initial viral infection. To examine this question. Finally, it should be noted that, in minimize lung cancer as a confounder, Luo and colleagues this study population, more than half of patients with lung assessed the outcomes of concurrent COVID-19 and lung cancer and COVID-19 were hospitalized and almost half of cancer in 69 consecutive patients at a single institution in those hospitalized died, emphasizing the need for studies to New York City. They performed manual annotation, includ- better understand risk factors and the disease course in this ing collecting data from a detailed self-reported smoking sur- group. n vey. PD-1 blockade was not a notable risk factor for increased COVID-19 severity or death among these patients, regardless See article, p. 1121.

Anti-EGFR Overcomes kRASG12C-Inhibitor Resistance in Colorectal Cancer

• KRASG12C inhibition is effective in some • KRAS G12C-mutant colorectal cancer cells • Inhibition of EGFR plus KRASG12C was KRASG12C-mutant cancers, but not had higher basal activation of the up- effective in colorectal cancer cells and KRASG12C-mutant colorectal cancer . stream receptor tyrosine kinase EGFR . patient-derived organoids and xenografts .

Although KRASG12C inhibition of upstream receptor tyrosine kinases, including EGFR. Cor- has shown effi cacy in patients respondingly, treatment of KRASG12C-mutant colorectal cancer with KRASG12C-mutant non– cells with the EGFR inhibitor cetuximab sensitized the cells to small cell lung cancer (NSCLC), AMG510, and cetuximab plus AMG510 treatment inhibited results have been less promis- cell proliferation and was cytotoxic in a colorectal cancer cell ing in patients with KRASG12C- line with acquired resistance (via KRASG12C mutation) to the mutant colorectal cancer. To under- EGFR antibody panitumumab. Extending these fi ndings, com- stand the mechanism underlying bination treatment with cetuximab plus AMG510 exerted syn- KRASG12C-inhibitor resistance in ergistic proliferation suppression in patient-derived organoids KRASG12C-mutant colorectal can- representing KRASG12C-mutant colorectal cancer, and patient- cer, Amodio, Yaeger, Arcella, and colleagues started by testing derived xenograft experiments using tumors from two patients the effects of the KRASG12C inhibitor AMG510 in KRASG12C- with KRASG12C-mutant colorectal cancer demonstrated that mutant NSCLC and colorectal cancer cell lines. This revealed cetuximab plus AMG510 led to marked or even complete that AMG510 treatment did not result in sustained inhibition tumor shrinkage. Together, these results provide insight into of phosphorylation of the downstream kinase ERK in colo- the reason behind the low effi cacy of KRASG12C inhibition in rectal cancer cells—instead, phospho-ERK levels rebounded KRASG12C-mutant colorectal cancer and suggest a therapeutic in colorectal cancer but not NSCLC cells after exposure to strategy that may be useful for overcoming this resistance. n AMG510. Further investigation revealed that the colorectal cancer cells, unlike the NSCLC cells, had high basal activation See article, p. 1129.

August 2020 CANCER DISCOVERY | 1079

Surmountable JAK1/2 and B2M Mutations Confer Anti–PD-1 Resistance

• JAK1 , JAK2, or B2M loss-of-function • A TLR9 agonist or an IL2 agonist • Mechanism-informed treatments mutations caused resistance to anti– overcame resistance in JAK1/2- or based on TLR9 or IL2 may be of inter- PD-1 therapy in colon cancer models . B2M-mutant tumors, respectively . est for cancers resistant to anti–PD-1 .

Loss-of-function mutations in resistance to anti–PD-1 treatment, with JAK1- and JAK2- JAK1/2 (encoding JAK1 and knockout tumors lacking IFNγ signal amplifi cation, and JAK2, tyrosine kinases involved in B2M-knockout tumors losing surface MHC antigen expres- IFN signaling) and B2M (encod- sion and not being recognized by T cells. In this model,

ing β2 microglobulin, a compo- JAK1/2 knockout–induced resistance could be overcome by nent of the MHC class I complex) combining intratumoral TLR9-agonist administration with are implicated in resistance of anti–PD-1 via reactivation of IFN signaling. In the B2M- cancers to anti–PD-1 therapy. To knockout model, resistance could be ameliorated by adding better understand the mecha- the IL2 agonist bempegaldesleukin to anti–PD-1 via natural nisms underlying resistance, killer–mediated responses. Importantly, the TLR9 agonist or Torrejon and colleagues fi rst investigated the effects ofJAK1 , bempegaldesleukin could also alleviate resistance in a mouse JAK2, or B2M knockout in human melanoma cell lines. model of melanoma that exhibits primary resistance to anti– JAK1 or JAK2 knockout caused insensitivity to IFN-mediated PD-1. Together, these results provide further evidence for the cytotoxicity via reduced IFN-induced transcription, whereas role of JAK1/2 and B2M in resistance to anti–PD-1 and sup- B2M knockout did not affect IFN sensitivity but prevented port mechanism-informed therapies that are currently being melanoma cells from being recognized by antigen-specifi c investigated in clinical trials of patients with resistance to T cells due to loss of cell-surface expression of MHC class PD-1 blockade therapy. n I. In a mouse model of colon adenocarcinoma with high mutational burden, JAK1, JAK2, or B2M knockout caused See article, p. 1140.

Bempegaldesleukin plus Nivolumab Is Safe in Multiple Malignancies

• The IL2 pathway agonist bempegal- • In 38 patients with advanced mela- • Response correlated with higher T-cell desleukin plus anti–PD-1 therapy with noma, renal cell carcinoma, or non–small infiltration and clonality, consistent nivolumab was tested in a phase I trial . cell lung cancer, treatment was safe . with bempegaldesleukin’s mechanism .

Although immune-checkpoint 40.5% experienced partial responses, and the median dura- inhibitors produce favorable tion of response was not reached after a median follow-up response rates in several cancers, period of 18 months. Consistent with the proposed mecha- these agents are not always effec- nism for bempegaldesleukin, T-cell infi ltration and clonality tive, perhaps sometimes in part were increased by week three of treatment in tumors that due to low levels of tumor-infi l- responded to the treatment, an observation that warrants trating lymphocytes. Based on further study in larger trials. With regard to safety and toler- evidence that the IL2 pathway ability, all patients experienced at least one treatment-emer- agonist bempegaldesleukin can gent adverse event, most commonly fl u-like symptoms, rash, promote proliferation and acti- fatigue, pruritus, arthralgia, decreased appetite, or headache, vation of CD4+ and CD8+ T cells as well as natural killer cells and there were no treatment-related deaths. Based on the in the tumor microenvironment, Diab, Tannir, Bentebibel, results of this study, the trial has been expanded to include and colleagues conducted a phase I trial of bempegaldesleu- patients with other tumor types; additionally, treatment with kin plus the PD-1 antibody nivolumab in 38 patients with bempegaldesleukin plus nivolumab is now being evaluated in immunotherapy-naïve advanced melanoma, renal cell carci- phase II and III trials including patients with various malig- noma, or non–small cell lung cancer (11, 22, and 5 patients, nancies. n respectively). Among the 37 patients for whom effi cacy evalu- ation was conducted, 18.9% attained complete responses and See article, p. 1158.

1080 | CANCER DISCOVERY August 2020 AACRJournals.org

Targetable Mutations Occur in CDk4/6 Inhibitor–Resistant Breast Cancer

• Genomic alterations in RB1, AURKA, and • These alterations were found in patient • In a phase I trial of an AURKA inhibitor, others correlated with CDK4/6-inhibitor tumors and many occurred with pro- a patient with CDK4/6 inhibitor– resistance in HR+HER2− breast cancer . longed CDK4/6-inhibitor treatment in vitro . resistant disease had a response .

CDK4/6 inhibitors are useful chemistry showed that some resistant tumors had lost ER for the treatment of hormone expression. In vitro, CRISPR–Cas9-mediated knockout of RB1 receptor–positive (HR+), HER2− or lentiviral overexpression of AKT1, KRASG12D, AURKA, or breast cancer, but primary resist- CCNE2 rendered HR+HER2− breast cancer cells resistant to ance and acquired resistance are CDK4/6 inhibition. Further, HR+HER2− breast cancer cells problematic, and the mecha- cultured with CDK4/6 inhibitors until the development of nisms that drive resistance are resistance exhibited genetic alterations in RB1, KRAS, AURKA, not fully understood. Wander, or CCNE2. Highlighting the potential clinical relevance of Cohen, Gong, and colleagues per- these fi ndings, one patient with metastatic HR+HER2− breast formed whole-exome sequencing cancer that recurred after more than three years of benefi t on 59 biopsies from 58 patients with CDK4/6 inhibitor– from a CDK4/6 inhibitor and letrozole was enrolled in a treated, HR+HER2− metastatic breast cancer, including 18 phase I clinical trial of an AURKA inhibitor, which led to biopsies from tumors sensitive to CDK4/6 inhibition, 28 prolonged disease stabilization. In summary, this work eluci- from tumors intrinsically resistant to CDK4/6 inhibition, dates several previously unknown mechanisms of resistance and 13 from tumors with acquired resistance to CDK4/6 to CDK4/6 inhibition in breast cancer and provides evidence inhibition. This analysis identifi ed several genomic altera- that many of these mechanisms may be clinically exploit- tions that may confer resistance, including loss of the tumor able. n suppressor gene RB1 and activating alterations in AKT1, RAS, AURKA, CCNE2, ERBB2, and FGFR2; further, immunohisto- See article, p. 1174.

Amivantamab Inhibits Growth of EGFR Exon 20 Insertion–Driven NSCLC

• Amivantamab was active in EGFR exon • This EGFR–MET-targeted bispecific • Patients in a phase I trial with EGFR exon 20 insertion–driven non–small cell lung antibody induced EGFR and MET down- 20 insertion–driven NSCLC showed cancer (NSCLC) in vitro and in vivo . regulation and programmed cell death . promising responses to amivantamab .

Although non–small cell lung vantamab. Mechanistically, amivantamab treatment led to cancers (NSCLC) harboring internalization and subsequent downregulation of EGFR and diverse EGFR-activating muta- MET as well as induction of antibody-dependent cell-medi- tions often respond to EGFR- ated cytotoxicity. In vivo, xenografts derived from EGFR exon directed tyrosine kinase inhibi- 20 insertion–driven cell lines or patient-derived cells were also tors (TKI), NSCLCs driven by sensitive to amivantamab, displaying reduced tumor volume EGFR exon 20 insertions gen- following amivantamab treatment. Finally, emphasizing the erally do not respond to these potential clinical relevance of these fi ndings, early results targeted therapies. Yun and col- from an ongoing phase I trial of amivantamab in patients leagues investigated the use of with advanced NSCLC have shown that amivantamab may the EGFR–MET-targeted bispecifi c antibody amivantamab, have antitumor activity in patients with EGFR exon 20 inser- which has shown early evidence of effi cacy in some types of tion–driven disease, with promising reductions in tumor EGFR-mutant NSCLC, in EGFR exon 20 insertion–driven volume observed. Collectively, this work demonstrates the NSCLC. In cell lines bearing a diverse range of EGFR exon 20 potential value of amivantamab in patients with EGFR exon insertions, amivantamab inhibited proliferation to a greater 20 insertion–driven NSCLC, a disease subtype with limited extent than TKIs by promoting apoptosis. Additionally, pri- treatment options. n mary cell cultures and organoids grown from patient tumors with EGFR exon 20 insertions were also sensitive to ami- See article, p. 1194.

August 2020 CANCER DISCOVERY | 1081

Differing Immune-Cell Subsets Underlie Sex Disparities in Glioblastoma

• Sex-based differences in populations of • Monocytic and granulocytic myeloid- • These differences were associated with suppressive immune-cell subsets were derived suppressor cells were enriched treatment responses and observed in seen in mouse glioblastoma models . in males and females, respectively . patients, implying clinical relevance .

Disparities in immune sys- to be due to rapid proliferation of monocytic MDSCs. Gene- tem functions between male and expression profi ling of MDSC subsets from bone marrow of female patients may underlie male and female mice followed by a network-medicine analy- some of the observed sex differ- sis identifi ed potential susceptibilities of monocytic MDSCs ences in cancer incidence, prog- to antiproliferative drugs and granulocytic MDSCs to IL1 nosis, and treatment response, pathway inhibitors. Consistent with these predictions, the but this subject has been scarcely antiproliferative agent fl udarabine extended survival in male explored in glioblastoma. Bayik but not female glioblastoma-bearing mice, whereas anti-IL1β and colleagues found that mono- extended survival in female but not male glioblastoma-bearing cytic myeloid-derived suppressor mice. Supporting the clinical relevance of these fi ndings, glio- cells (MDSC) were enriched in the tumors of male mice blastomas from male patients were enriched with proliferative but not female mice following intracranial glioblastoma-cell monocytic MDSCs, and high expression of genes represent- injection. Additionally, granulocytic MDSCs were enriched ing a granulocytic MDSC gene signature or IL1B (encoding in the peripheral blood of female mice but not male mice IL1β) was associated with poor prognosis in female patients. after the tumor implantation. Notably, depletion of granulo- Together, this work reveals a previously unknown explanation cytic MDSCs with neutralizing antibodies provided a survival for sex differences in glioblastoma and demonstrates how this advantage in female but not male glioblastoma-bearing mice, knowledge may be therapeutically exploitable. n and monocytic MDSCs could not be depleted using neutralizing antibodies in mice of either sex, an effect that appeared See article, p. 1210.

INPP4B Loss Promotes Triple-Negative Breast Cancer via EGFR Signaling

• The lipid phosphatase INPP4B was a • INPP4B loss activated the PI3K–AKT • Lack of INPP4B reduced EGFR traffick- tumor suppressor in a mouse model and MEK–ERK pathways, causing sen- ing to late endosomes, causing EGFR of triple-negative breast cancer . sitivity to PI3K and MEK inhibitors . buildup and higher EGFR signaling .

Loss-of-function mutations in led to increased susceptibility to PI3K and MEK inhibitors. INPP4B, encoding a member of Consistent with INPP4B’s established lipid phosphatase activ-

the PI3K–AKT pathway that ity on PI(3,4)P2, buildup of PI(3,4)P2 as a constituent of intra- dephos phorylates PI(3,4)P2 to cellular endocytic vesicles, but not the plasma membrane, was PI(3)P, have been observed in observed in INPP4B-defi cient cells. Notably,INPP4B -defi cient triple-negative breast cancer cells also exhibited delayed degradation of the upstream recep- (TNBC); however, the role of tor tyrosine kinases EGFR and MET, and INPP4B loss also these mutations is unclear. In a caused increased EGFR levels in tumors. Mechanistically, this mouse model of TNBC, Liu and could be explained by an observed reduction in EGFR traf- colleagues found that INPP4B fi cking from early endosomes to late endosomes and then knockout led to increased penetrance of the TNBC pheno- lysosomes in INPP4B-defi cient cells, delaying EGFR degrada- type, providing evidence for INPP4B’s role as a tumor-suppres- tion and leading to an increase in downstream signaling. In sor gene in this malignancy. Although INPP4B defi ciency can summary, this work provides support for the proposed role of impair DNA repair and lead to chromosomal instability, this INPP4B as a tumor-suppressor gene in TNBC and character- was not observed in this TNBC model. Instead, loss of INPP4B izes the mechanistic basis by which this occurs. n was associated with activation of the PI3K–AKT and MEK– ERK pathways. Consequently, INPP4B defi ciency in tumors See article, p. 1226.

In This Issue is written by Cancer Discovery editorial staff . Readers are encouraged to consult the original articles for full details .

1082 | CANCER DISCOVERY August 2020 AACRJournals.org

Cancer Discov 2020;10:1079-1082.

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